WO2009128390A1

WO2009128390A1 - Method for producing optically active cyanohydrin compound

Info

Publication number: WO2009128390A1
Application number: PCT/JP2009/057302
Authority: WO
Inventors: 中澤公一
Original assignee: 住友化学株式会社
Priority date: 2008-04-18
Filing date: 2009-04-03
Publication date: 2009-10-22
Also published as: AU2009237057A1; CN102007095A; US8309753B2; JP2009256262A; EP2264005B1; EP2264005A4; IL208303A0; JP5353046B2; EP2264005A1; US20110034718A1; IL208303A; TWI432403B; CN102007095B; TW201004907A; AU2009237057B2

Abstract

Disclosed is a method for producing an optically active cyanohydrin compound represented by formula (3) (wherein Q¹ and Q² are as defined below, and * represents that the carbon atom is the optically active center), which is characterized in that an aldehyde compound represented by formula (2) (wherein Q¹ and Q² independently represent an optionally substituted alkyl group having 1-6 carbon atoms or the like) is reacted with hydrogen cyanide in the presence of a silyl compound and an asymmetric complex which is obtained by reacting an optically active pyridine compound represented by formula (1) (wherein R¹ and R² independently represent a hydrogen atom, an alkyl group having 1-6 carbon atoms or the like, provided that R¹ and R² are not the same) with aluminum halide.

Description

Description Method for producing optically active cyanohydrin compound Technical Field

The present invention relates to a method for producing an optically active cyanohydrin compound. Background art

US Pat. No. 4,500,071 discloses that optically active m-phenoxymande mouth-tolyl is used as an intermediate for producing agricultural fungicides.

Optically active m-phenoxymandelonitrile is one of the optically active cyanohydrin compounds. The optically active cyanohydrin compound is produced by reacting aldehyde with hydrogen cyanide in the presence of an optically active vanadyl catalyst. There is a known method (see Special Table 2 0 0 4-5 3 3 4 90). On the other hand, an asymmetric complex is obtained by reacting aluminum chloride with an optically active bisoxazolyl pyridine compound, and an aldehyde compound and trimethylsilyl cyanide are reacted in the presence of the asymmetric complex. A method for producing an optically active cyanohydrin compound O-silyl ether is also known (see Tetrahedron: Asymmetry, Vol. 8, p. 1279 (1997)). Disclosure of the invention

The present invention

(In the formula, R ¹ and R ² independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbon atoms. R ¹ and R ² are never the same.)

In the presence of an asymmetric complex and a silyl compound obtained by reacting an optically active pyridine compound represented by the formula (2) with an aluminum halide,

(Wherein Q ¹ and Q ² are independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkoxy group having 1 to 4 carbon atoms, the number of carbon atoms, A 2-8 acyloxy group, an optionally substituted alkanesulfonyloxy group having 1 to 4 carbon atoms, an optionally substituted benzenesulfonyloxy group, a trialkylsilyloxy group having 1 to 10 carbon atoms Group or an optionally substituted aryloxy group having 6 to 10 carbon atoms.)

Formula (3) characterized by reacting hydrogen cyanide with

(In the formula, Q ¹ and Q ² represent the same meaning as described above, and * represents that the carbon atom is an optically active center.)

A process for producing an optically active cyanohydrin compound represented by:

<2> The production method according to 1>, wherein the silyl compound is a trialkylsilyl cyanide compound;

<3> The production method according to <1>, wherein the silyl compound is trimethylsilyl cyanide; <4> the production method according to any one of <1> to <3>, wherein the aluminum halide is aluminum chloride;

<5> One of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbon atoms. A manufacturing method according to any one of <1> to <4>;

<6> one of R ¹ and R ² is a hydrogen atom, one other is alkyl group or Ariru group with carbon number 6-1 0 1 to 6 carbon atoms <1> to the <4> The production method according to crab;

<7> Q ¹ is a hydrogen atom, and Q ² may be substituted, an alkyl group having 1 to 6 carbon atoms, an optionally substituted alkoxy group having 1 to 4 carbon atoms, or a carbon atom having 2 to 8 carbon atoms An acyloxy group, an optionally substituted alkanesulfonyloxy group having 1 to 4 carbon atoms, an optionally substituted benzenesulfonyloxy group, a trialkylsilyloxy group having 1 to 10 carbon atoms, or a substituted group. The production method according to any one of 1 to <6>, which is an aryloxy group having 6 to 10 carbon atoms, which may be

<8> Q ¹ is a hydrogen atom, and Q ² is an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted aryloxy group having 6 10 carbon atoms 1> to <6> The manufacturing method according to any one of

<9> The amount of the asymmetric complex used is from 0.05 to 1 mol per 1 mol of the aldehyde compound represented by the formula (2) in terms of aluminum atom, The production method according to any one of the above;

<1 0> The amount of the silyl compound used is any one of <1> to <9>, which is 0.01 to 0.5 mol with respect to 1 mol of the aldehyde compound represented by the formula (2) <1 1> The amount of hydrogen cyanide used is 1.1 to 3 mol per 1 mol of the aldehyde compound represented by formula (2). The manufacturing method as described above is provided. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the aluminum halide include aluminum chloride and aluminum bromide. Aluminum chloride is preferred. A commercially available aluminum halide may be used, or an aluminum halide produced according to a known method may be used.

-

In which R ¹ and R ² are independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, carbon, It represents an aryl group having 6 to 10 carbon atoms or an aralkyl group having 7 to 11 carbon atoms. However, R ¹ and R ² are not the same.

Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec_butyl group, and a tert-butyl group. An alkyl group having 1 to 4 carbon atoms is preferable.

Examples of the aryl group having 6 to 10 carbon atoms include a phenyl group and a naphthyl group. The ru group is preferred.

Examples of the aralkyl group having 7 to 11 carbon atoms include benzyl group and naphthylmethyl group.

An optically active pyridine in which one of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbon atoms. Compound (1) is preferred, and ^one of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms. Compound (1) Is more preferable. Optically active pyridine compounds (1) include optically active 2, 6_bis (4-methyloxazol-2-yl) pyridine, optically active 2, 6-bis (4-ethyloxyzol-2-yl). ) Pyridine, optically active 2,6-bis (4-isopropyloxazol-2-yl) Pyridine, optically active 2,6-bis (4-tert _ butyloxazole-2-I) Pyridine, optically active 2, 6-bis (4-sec butyloxazole-2-yl) Pyridine, optically active 2, 6-bis (4-isoptyloxazo-Lu 2) —Yl) Pyridine, optically active 2, 6-bis (4-phenyloxazole— 2-yl) Pyridine, optically active 2, 6-bis (4-naphthyloxazol 1- ^ Γ) ) Pyridine, optically active 2, 6_bis (4-benzyloxazole-2-yl) Pyridine, optically active 2 3,6-Bis [4 one (naphth Rumechiru) Okisazo one rule 2 I le] pyridine.

The optically active pyridine compound (1) may be in the S form or the R form. Further, a mixture of S-form and R-form, in which any one of S-form and R-form is contained more than the other may be used.

As the optically active pyridine compound (1), a commercially available product may be used, or a product produced according to a known method described in JP-A No. 2-36181, etc. may be used.

The amount of the optically active pyridine compound (1) to be used is generally 0.8-5 mol, preferably 1-2 mol, per 1 mol of aluminum halide.

An asymmetric complex can be obtained by reacting an aluminum halide with an optically active pyridine compound (1). Such a reaction is usually carried out in the presence of a solvent.

Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloromethane and chloroform, and aromatic hydrocarbon solvents such as benzene, toluene, xylene, black benzene and dichlorobenzene. The amount of solvent used is not limited, but is usually 10 to 500 parts by weight per 1 part by weight of the halogenated aluminum. Such a reaction is preferably carried out in the absence of water. The reaction is preferably carried out in an atmosphere of an inert gas such as argon or nitrogen.

The reaction temperature is usually −20 ° C. or higher, preferably 15 to 50 ° C. When aromatic hydrocarbons are used as the solvent, it is preferable to carry out the reaction at 50 ° C. or lower in terms of suppressing the progress of side reactions.

The reaction time is usually 1 minute to 5 hours.

Thus, a mixture containing an asymmetric complex can be obtained. The obtained mixture may be used as it is for the reaction of an aldehyde compound represented by the formula (2) described later and hydrogen cyanide, or an isolation means such as concentration. The asymmetric complex may be taken out from the mixture and used. Usually, the obtained mixture containing the asymmetric complex is used as it is for the reaction of the aldehyde compound represented by the formula (2) with hydrogen cyanide.

In the formula of aldehyde compound (hereinafter abbreviated as aldehyde compound (2)), Q ¹ and Q ² are each independently a hydrogen atom or an optionally substituted alkyl having 1 to 6 carbon atoms. An optionally substituted alkoxy group having 1 to 4 carbon atoms, an optionally substituted acyloxy group having 2 to 8 carbon atoms, an optionally substituted alkanesulfonyloxy group having 1 to 4 carbon atoms, It represents a benzenesulfonyloxy group which may be substituted, a trialkylsilyloxy group having 1 to 10 carbon atoms or an aryloxy group having 6 to 10 carbon atoms which may be substituted.

'Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group.

Such an alkyl group may be substituted with at least one substituent, and examples of the substituent include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like having 1 to 4 carbon atoms. An alkylthio group having 1 to 4 carbon atoms such as a methylthio group, an ethylthio group, a propylthio group, or a butylthio group; a phenoxy group, a 6 to 12 carbonyl aryloxy group such as a 2,5-dimethylphenoxy group; a phenylthio group , 2, 5-dimethylphenylthio group and the like having 6 to 12 carbon atoms; methanesulfonyl group, trifluoromethanesulfonyl group, chloromethyl C1-C4 alkylsulfonyl group which may be substituted with a halogen atom such as tansulfonyl group; Nitro group such as benzenesulfol group, p-toluenesulfoninole group, o-two-ended benzenesulfonyl group Or a benzenesulfonyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms; and the like.

Examples of the alkyl group substituted with such a substituent include a methoxymethyl group, an ethoxymethyl group, a methylthiomethyl group, a phenylthiomethyl group, a 2,5-dimethylphenoxymethyl group, a methanesulfonylmethyl group, and a chloromethanesulfonylmethyl group. Group, trifluoromethanesulfonylmethyl group, benzenesulfonylmethyl group, 4-methylbenzenesulfonylmethyl group, 4-12 trobenzenesulfonylmethyl group, 2-methoxychetyl group, 2-ethoxyethyl group, 2- (methylthio) ethyl group, Examples include 2- (phenylthio) ethyl group, 2_methanesulfonylethyl group, 2-trifluoromethanesulfonylethyl group, 2-benzenesulfonylethyl group, 2- (4-nitrobenzenesulfonyl) ethyl group, and the like. .

Examples of the alkoxy group having 1 to 4 carbon atoms include the same ones as described above. Such an alkoxy group may be substituted with at least one substituent, and examples of the substituent include a halogen atom such as a fluorine atom.

Examples of the alkoxy group substituted with such a substituent include a difluoromethoxy group, a trifanolomethoxy group, a pentafanololethoxy group, a 1,1,1,3,3,3-hexafluoro-2-propoxy group, and the like. .

Examples of the acyloxy group having 2 to 8 carbon atoms include acetoxy group, propionyloxy group, petityloxy group, bivalyloxy group, neopentanecarbonyloxy group, benzoyloxy group, phenylacetoxy group, naphthylacetoxy group, and the like. It is done.

Examples of the alkyl sulfonyloxy group having 1 to 4 carbon atoms include a methanesulfonyloxy group. The alkanesulfonyloxy group may be substituted with at least one substituent, and examples of the substituent include halogen atoms such as a fluorine atom. Examples of the alkanesulfonyloxy group substituted with such a substituent include a trifluoromethanesulfoxy group.

Examples of the optionally substituted benzenesulfonyloxy group include a benzenesulfonyloxy group substituted with an alkyl group having 1 to 4 carbon atoms such as a benzenesulfonoxy group and a p-toluenesulfonyloxy group, o _A benzenesulfonyloxy group substituted with a ditro group such as a nitrobenzenesulfo2 / reoxy group or a p-nitrobenzene sulfonyloxy group.

Examples of the C1-C10 trialkylsilyloxy group include a trimethylsilyloxy group, Examples thereof include a triethylsilyloxy group, a triprovir silyloxy group, and a tert-butyldimethylsilyloxy group.

Examples of the aryloxy group having 6 to 10 carbon atoms include a phenoxy group and a naphthyloxy group. Such an aryloxy group may be substituted with at least one substituent, and examples of the substituent include an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and a halogen atom. Examples of the aryloxy group substituted by such a substituent include 4-methylphenoxy group, 2-methylphenoxy group, 2,4-dimethylphenoxy group, 2,4-di-tert-butylphenoxy group, 4-methoxyphenoxy group, 4_Ethoxyphenoxy group, 2-fluorophenoxy group, 4-fluorophenoxy group, pentafluorophenoxy group and the like.

Q ¹ is a hydrogen atom and Q ² is an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkoxy group having 1 to 4 carbon atoms, an acyl group having 2 to 8 carbon atoms, substitution An optionally substituted alkanesulfonyloxy group having 1 to 4 carbon atoms, an optionally substituted benzene sulfonyloxy group, a trialkylsilyloxy group having 1 to 10 carbon atoms, an optionally substituted group, or an optionally substituted group. Preferred is an aldehyde compound (2) which is a good aryl group having 6 to 10 carbon atoms, Q ¹ is a hydrogen atom, Q ² may be substituted alkyl group having 1 to 6 carbon atoms or substituted The aldehyde compound (2) which is an aryloxy group having 6 to 10 carbon atoms may be more preferable. Examples of the aldehyde compound (2) include benzaldehyde, o-methylbenzaldehyde, p_methylbenzaldehyde, o-ethylbenzaldehyde, o-isopropinorebenzaldehyde, p-tert —Butylbenzaldehyde, o—Methoxymethylbenzaldehyde, o— (2—Methoxystil) Benzaldehyde, o— (Ethoxymethyl) Benzaldehyde, o— (Methylthiomethyl) benzaldehyde, o— (2 —Methylthioethyl) benzaldehyde, o— (Ethylthiomethyl) benzaldehyde, o _ (phenoxymethyl) benzaldehyde, o _ (2,5-dimethylphenoxymethyl) benzaldehyde, p—

(2,5-Dimethylphenoxymethyl) benzaldehyde, o— (Phenylthiomethyl) benzaldehyde, o _ (2,5-Dimethylphenylthiomethyl) benzaldehyde, o Monomethanesulfonylmethyl benzaldehyde, o-Triflule O-methanesulfonylmethyl benzaldehyde, o_benzenesulfonylmethyl benzaldehyde, o— (p-tolenylenesulfonylmethyl) benzaldehyde, o— (o— nitrobenzenesulfonylmethyl) benzaldehyde, o— methoxybenzaldehyde , M-methoxybenzaldehyde, p -Methoxybenzaldehyde, o-Ethoxybenzaldehyde, o-Isopropoxybenzaldehyde, o-Difluoromethoxybenzaldehyde, o-Trifluoromethoxybenzaldehyde, o-Pentafluoroethoxybenzaldehyde, o — (1, 1, 1, 3, 3, 3—Hexafluoro-2-propoxy) benzaldehyde, o-acetoxybenzaldehyde, p-acetoxybenzaldehyde, o-propionyloxybenzaldehyde O-Butyryloxybenzaldehyde, o-Bivaloyloxybenzaldehyde, o-Phenylacetoxybenzaldehyde, p-Phenylenoacetoxybenzaldehyde, o-Na-Futylacetoxybenzaldehyde O-Methanesulfonyloxybenzaldehyde, o-Trifluoromethane Rusulfonyloxybenzaldehyde, o_ (p-toluenesulfonyloxy) Benzaldehyde, o— (o-nitrobenzenesulfonyloxy) benzanolide, o— (p-nitrobenzenesulfonyloxy) benzaldehyde O-trimethylsilyloxybenzaldehyde, o-triethylsilyloxybenzaldehyde, o-triprovirsilyloxybenzaldehyde, o-tert-butyldimethylsilyloxybenzaldehyde / ^ dealdehyde, o —Phenoxybenzaldehyde, m—phenoxybenzaldehyde, o—naphthylbenzaldehyde, o— (4-methylphenoxy) benzaldehyde, o _ (2-methylphenoxy) Benzaldehyde, o— (2,4-Dimethylphenoxy) Benzaldehyde, o— (2, 4-Didi tert- (Butylphenoxy) Benzaldehyde, o— (4-Methoxyphenoxy) Benzaldehyde, o_ (4-Ethoxyphenoxy) Benzaldehyde, o_ (2-Fluorophenoxy) Benzaldehyde, o— (4 —Fluorophenoxy) Benzaldehyde, o-pentafluorophenoxybenzaldehyde, o _ (2, 6-dimethylphenoxymethyl) p_ (Methoxymethyl) benzaldehyde, o— (2, 6-dimethylphenoxy P- (methylthiomethyl) benzaldehyde, o- (2,6-dimethylphenoxymethyl) p- (phenylthiomethyl) benzaldehyde, o- (2,6-dimethylphenoxymethyl) ) _P—Trifluoromethyloxybenzaldehyde, o— (2,6-Dimethylphenoxymethyl) Mono-p-pentafluoro ethoxyben Aldehydes, o-(2, 6- dimethyl phenoxyethanol methyl) Single p_ Aseto carboxymethyl benz aldehyde arsenide de, o-(2, 6- dimethyl phenoxyethanol methyl) Single p- Benzoiruo carboxymethyl benz aldehyde arsenide de. One (2,6-dimethylphenoxymethyl) One p-trimethylsilyloxybenzaldehyde, o— (2,6-Dimethylphenoxymethyl) One p-triethylsilyloxybenzaldehyde, o — (2,6-Dimethylphenoxymethyl) _p_ (tert-Butyldimethylsilyloxy) benzaldehyde, o— (2,6-Dimethylphenoxymethyl) 1 p-phenoxybenzaldehyde,. One (2, 6-dimethylphenol) Xymethyl) _p-pentafluorophenoxybenzaldehyde.

As the aldehyde compound (2), a commercially available product may be used, or a product produced according to a known method may be used.

Commercially available hydrogen cyanide may be used, or hydrogen cyanide produced according to a known method may be used.

Gaseous hydrogen cyanide or liquid hydrogen cyanide may be used. Alternatively, a hydrogen cyanide solution obtained by dissolving hydrogen cyanide in a solvent may be used. Solvents for dissolving hydrogen cyanide include dichloromethane, 1,2-dichloromethane, halogenated hydrocarbons such as chloroform, benzene, toluene, xylene, aromatic hydrocarbons such as benzene, dichlorobenzene, tert — Examples include ether solvents such as butyl methyl ether, jetyl ether, and tetrahydrofuran. The amount of the solvent used may be 1 part by weight or more with respect to 1 part by weight of hydrogen cyanide.

The amount of hydrogen cyanide used may be 1 mol or more, preferably 1.:! To 3 mol, relative to 1 mol of the aldehyde compound (2).

The amount of the asymmetric complex to be used is usually 0.001 mol or more, preferably 0.005 to 1 mol, more preferably 0.001 mol or more per 1 mol of the aldehyde compound (2) in terms of aluminum atom. 0 1 to 1 mole.

Examples of silyl compounds include halogenated trianolsilylsilyls such as trimethylsilyl chloride and triethylsilyl chloride, trialkylsilyl cyanides such as trimethylsilyl cyanide, silylamines such as hexamethyldisilazane, tris (trimethylsilinore) amine, and the like. Trialkylsilyl cyanide is preferred, and trimethylsilyl cyanide is more preferred. The amount of the silyl compound to be used is usually 0.1 to 0.5 monole, preferably 0.05 to 0.2 mol, per 1 mol of the aldehyde compound (2).

The reaction between the aldehyde compound (2) and hydrogen cyanide is usually carried out in the presence of a solvent. Solvents include aromatic hydrocarbon solvents such as xylene, toluene, black benzene, o-dichloro benzene, and benzene, aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and cyclohexane, tetrahydrofuran, and benzene. Examples thereof include ether solvents such as tilether, tert-butyl methyl ether and cyclopentyl methyl ether, and halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform. These may be used alone or in admixture of two or more. Of these, halogenated hydrocarbon solvents are preferred, and dichloromethane is more preferred.

The amount of solvent used is not limited, but from the viewpoint of economy, the aldehyde compound (2) 1 part by weight On the other hand, it is preferably 100 parts by weight or less.

Such a reaction is usually carried out by mixing an asymmetric complex, a silyl compound, an aldehyde compound (2) and hydrogen cyanide, and the mixing order thereof is not limited. For example, an aldehyde compound (2) and a silyl compound may be added to a mixture containing an asymmetric complex adjusted to a predetermined reaction temperature, and hydrogen cyanide may be added, or the asymmetric complex and aldehyde compound (2) may be added. The mixture obtained by mixing the silyl compound and the silyl compound may be adjusted to a predetermined reaction temperature, and hydrogen cyanide may be added to the mixture. The silyl compound may be added to the mixture containing the asymmetric complex adjusted to the predetermined reaction temperature, and the aldehyde compound (2) and hydrogen cyanide may be added simultaneously in parallel. Hydrogen cyanide and silyl compound may be added to the mixture containing the prepared asymmetric complex, and further aldehyde compound (2) may be added. The mixture obtained by mixing the asymmetric complex and hydrogen cyanide may be adjusted to a predetermined reaction temperature, and the aldehyde compound (2) may be added to the mixture, or the aldehyde adjusted to the predetermined reaction temperature may be added. To the compound (2), an asymmetric complex and a silyl compound may be added, and further hydrogen cyanide may be added. A mixture obtained by mixing the aldehyde compound (2), the asymmetric complex and the silyl compound may be adjusted to a predetermined reaction temperature, and hydrogen cyanide may be added to the mixture, or the predetermined reaction temperature may be increased. Hydrogen cyanide and a silyl compound may be added to the prepared aldehyde compound (2), and an asymmetric complex may be further added. A mixture obtained by mixing the aldehyde compound (2), hydrogen cyanide and silyl compound may be adjusted to a predetermined reaction temperature, and an asymmetric complex may be added to the mixture, or the aldehyde compound (2) and The mixture obtained by mixing the silyl compound may be adjusted to a predetermined reaction temperature, and hydrogen cyanide and the asymmetric complex may be added to the mixture simultaneously. Among them, it is preferable to add the aldehyde compound (2) and the silyl compound to the mixture containing the asymmetric complex adjusted to a predetermined reaction temperature, and further add hydrogen cyanide.

The reaction temperature of the reaction between the aldehyde compound (2) and hydrogen cyanide is usually from 80 to 50 ° C.

From the viewpoint of the yield of the optically active cyanohydrin compound (hereinafter abbreviated as optically active cyanohydrin compound (3)) and the enantiomeric excess, 0 to 35 ° C. is preferable. Such a reaction may be performed under normal pressure or under pressure.

The progress of the reaction can be confirmed by ordinary analytical means such as gas chromatography, high performance liquid chromatography, and NMR.

Thus, a reaction mixture containing the optically active cyanohydrin compound (3) is obtained. For example, the reaction mixture is washed with an aqueous solution of an acid such as water or hydrochloric acid, and the obtained organic layer is concentrated. The optically active cyanohydrin compound (3) can be taken out. The extracted optically active cyanohydrin compound (3) may be further purified by ordinary purification means such as recrystallization, distillation, column chromatography, or mouthmatography. The optically active cyanohydrin compound (3) thus obtained includes optically active mandelonitrile, optically active o-methylmandelonitrile, optically active p-methylmandetrinitrile, optically active o-ethyl. Mandelonitrile, optically active o-isopropylmandello, nitrile, optically active p_tert-butylmandelonitrile, optically active o_ (methoxymethyl) mandelonitrile, optically active o— (2— Methoxetyl) mandelonitrile, optically active o- (ethoxymethyl) mandelonitrile, optically active o- (methylthiomethyl) mandelonitrile, optically active o_ (2-methylthioethyl) mandelonitrile, Optically active o- (Ethylthiomethyl) mandelonitrile, Optically active 0— (Phenoxymethyl) Mandelonitrile Optically active o _ (2,5_dimethylph: n-noxymethyl) Mandero nitrile, Optically active p_ (2,5-Dimethylphenoxymethyl) Mandelonitrile, Optically active o_ (phenylthiomethyl) Mandelonitrile, optically active o— (2,5-dimethylmethylthiomethyl) Mandelonitrile, optically active o— (methanesulfonylmethyl) Mandelonitrile, optically active o_ (trifluoromethanesulfonylmethyl) Mandeloni Tolyl, optically active o_ (benzenesulfonylmethyl) mandelonitrile, optically active o

-(p-toluenesulfonylmethyl) mandelonitrile, optically active O- (O-nitrobenzenesulfonylmethyl) mandelonitrile, optically active o-methoxymandelonitrile, optically active m-methoxymandelo Nitrile, optically active p-methoxymandelonitrile, optically active o-ethoxymandelonitrile, optically active o-isopropoxymandelonitrile, optically active o- (difluoromethoxy) mandelonitrile, optically active O-Trifluoromethoxymandelonitrile, optically active o-pentafluoroethoxymandelonitrile, optically active o- (1, 1, 1, 3, 3, 3, 3-hexafluoro-2-propoxy) mandelonitrile Optically active o-acetoxymandelonitrile, optically active p-acetoxysimande-tolyl, optically active O-propionyloxymandelonitrile, optically active o-Butyryloxymandelonitrile, optically active o-Bivaloyloxymandelonitrile, optically active o_ (Phenylacetoxy) mandelonitrile, optically active p_ (Phenylacetoxy) mandelonitrile, optical Active o_ (naphthylacetoxy) mandelonitol, optically active o-methanesulfonyloxymandelonitrile, optically active o-trifluoromethanesulfonyloxymandelonitrile, optically active o- (p-toluenesulfo Niloxy) mandelonitrile, optically active o_ (o _ nitrobenzenesulfonyloxy) mandelonitrile, optically active O— (o _ nitrobenzenesulfonyloxy) mandelonitrile, optically active o-trimethylsilyloxymandelonitrile, Optically active o_tritylsilyloxymandelonite , Optically active o_triprovirsilyloxymandelonitrile, optically active o_ (tert-butyldimethylsilyloxy) mandelonitrile, optically active o-naphthyloxymandelonitrile, optically active o— (4 —Methylphenoxy) mandelonitrile, optically active o— (2—methylphenoxy) mandelonitrile, optically active o— (2,4-dimethylphenoxy) mandelonitrile, optically active o_ (2,4 Tert-Butylphenoxy) Mandelonitrinore, optically active o_ (4-methoxyphenoxy) Mandelonitrile, Optically active o— (4-Ethoxyphenoxy) Mandeloninitrile, Optically active o— ( 2-Fluorophenoxy) Mandelonitrile, optically active o-(4-Fluorophenoxy) Mandelonitrile, Optically active o-Pentafluorophenol Noxymandelonitrinore, optically active o- (2,6-dimethylphenoxymethyl) p- (methoxymethyl) mandelonitrile, optically active o- (2,6-dimethylphenoxymethyl) — P— (Methylthiomethyl) mandelonitrile, optically active o— (2, 6-dimethylphenoxymethyl) _p— (phenylthiomethyl) mandelonitrile, optically active o— (2, 6-dimethylphenoxymethyl) ) P-Trifluoromethoxymandelonitrile, optically active o_ (2,6-dimethylphenoxymethyl) _p-pentafluoroethoxymanderonitrile, optically active o- (2,6-Dimethyl Phenoxymethyl) mono-p-acetoxymandelonitrile, optically active o- (2,6-dimethylphenoxymethyl) mono-p-benzoyloxymandelonitrile, optically active o- (2, 6-dimethylphenoxymethyl) _p— trimethylsilyloxymandelonitrile, optically active o- (2, 6-dimethylphenoxymethyl) —p-triethylsilyloxymandelonitrile, optically active o— ( 2, 6-dimethylphenoxymethyl) p- (tert-butyldimethylsilyloxy) mandero-tolyl, optically active o_ (2,6-dimethylphenoxymethyl) mono-p-phenoxymandelonitrile, optically active o_ (2,6-Dimethylphenoxymethyl) _p—Pentafluoroenoxymandelonitrile etc. Example

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. The content was calculated based on the results of the high-speed liquid chromatography internal standard method. The enantiomeric excess was measured by high performance liquid chromatography (column: SUM I CH I RAL (registered trademark) OA-4900, manufactured by Sumika Chemical Analysis Co., Ltd., eluent: hexane ethanol). Example 1

To 3 OML necked flask, chloride Anoreminiumu 27mg and 2, 6-bis - obtained _c plus the (4-(S) phenylene Ruokisazo Ichiru one 2-I le) pyridine 9 Omg and 1 mL of dichloromethane While stirring the mixture, the internal temperature was adjusted to 0 ° C. to obtain a mixture containing an asymmetric complex. To this mixture, 1 g of 2- (2,5-dimethylphenoxymethyl) benzaldehyde, 41 mg of trimethylsilyl cyanide and 3 mL of dichloromethane were added. The resulting mixture was stirred at an internal temperature of 0 ° C. for 1 hour, and then hydrogen cyanide 17 Omg was added dropwise over 3 hours. The obtained mixture was stirred at 0 ° C. for 2 hours to obtain a reaction mixture containing optically active o- (2,5-dimethylphenoxymethyl) mandelonitrile.

2- (2,5-Dimethylphenoxymethyl) benzaldehyde conversion: 95% Optically active o- (2,5-Dimethylphenoxymethyl) Mandelonitrile enantiomeric excess: 88% ee (R body) Example 2

To a 10-OmL three-necked flask, 27 mg of aluminum chloride and 2,6-bis (4- (S) -phenyloxazole_2-yl) pyridine 9 Omg and dichloromethane 5 mL were added. While stirring the obtained mixture, the internal temperature was adjusted to 0 ° C. to obtain a mixture containing an asymmetric complex. To the mixture was added 2 g of 2- (2,5-dimethylphenoxymethyl) benzaldehyde, 0.2 g of trimethylsilyl cyanide and 15 mL of dichloromethane. The resulting mixture was stirred at an internal temperature of 0 ° C. for 1 hour, and then 0.83 g of hydrogen cyanide was added dropwise over 3 hours. The resulting mixture was stirred at 0 ° C. for 14 hours to obtain a reaction mixture containing optically active o- (2,5-dimethylphenoxymethyl) mande-tolyl.

2_ (2,5-Dimethylphenoxymethyl) benzaldehyde conversion: 51% Optically active o- (2,5-Dimethylphenoxymethyl) Mandelonitrile enantiomer excess Surplus rate: 85% ee (R body) Example 3

In Example 1, the reaction was carried out in the same manner as in Example 1 except that 45 mg of trimethylsilyl chloride was used in place of 1 mg of trimethylsilinole cyanide 4, and optically active o- (2,5-dimethylphenoxy was used. A reaction mixture containing (methyl) mandelonitrile was obtained.

2-(2,5-Dimethylphenoxymethyl) benzaldehyde conversion: 31% Enantiomer excess of optically active o_ (2,5-dimethylphenoxymethyl) mandelonitrile: 50% ee (R body) Example 4

In Example 1, the reaction was carried out in the same manner as in Example 1 except that 67 mg of hexamethyldisilazane was used instead of 4 mg of trimethylsilyl cyanide, and optically active o- (2,5-dimethylphenol was used. Enoxymethyl) A reaction mixture containing mandelonitrile was obtained.

2-(2,5-Dimethylphenoxymethyl) benzaldehyde conversion: 15% Optically active enantiomer excess of o_ (2,5-Dimethylphenoxymethyl) mandelonitrile: 68% ee (R body) Example 5

In Example 1, except that toluene was used instead of dichloromethane, the reaction was carried out in the same manner as in Example 1, and a reaction mixture containing optically active o- (2,5-dimethylphenoxymethyl) mandelonitrile was obtained. Obtained.

Conversion rate of 2- (2,5-dimethylphenoxymethyl) benzaldehyde: 95% Optically active o- (2,5-dimethylphenoxymethyl) Enantiomer excess of mande mouth-tolyl: 76% ee (R body) Example 6

In Example 1, 2, 6-bis (4- (S) -phenyloxazole-2-yl) pyridine 9 Omg instead of 2, 6-bis (4- (S) T sopropylo Except for using 72 mg of xazol-2-ynole) pyridine, the reaction was carried out in the same manner as in Example 1, and reaction containing optically active o_ (2,5-dimethylphenoxymethyl) mandelonitrile A mixture was obtained.

2- (2,5-Dimethylphenoxymethyl) benzaldehyde conversion: 95% Optically active o- (2,5-dimethylphenoxymethyl) Mandenitrile enantiomeric excess: 82% ee (R form) Example 7

In Example 1, 2, 6_bis (4- (S) — phenylene oxazol 2-yl) Instead of pyridine, 2, 6_ bis (4- (R) — phenylene oxazole 2 _ i The reaction was conducted in the same manner as in Example 1 except that pyridine was used to obtain a reaction mixture containing optically active o_ (2,5-dimethylphenoxymethyl) mandelonitrile.

Conversion rate of 2- (2,5-dimethylphenoxymethyl) benzaldehyde: 95% Enantiomeric excess of optically active o_ (2,5-dimethylphenoxymethyl) mandelonitrile: 84% ee (S body) Example 8

A 10 OmL three-necked flask was charged with 37 mg of aluminum chloride and 457 mg of 2,6-bis (4- (S) -phenyloxazole _2-yl) pyridine and 1 OmL of dichloromethane. The resulting mixture was adjusted to an internal temperature of 0 ° C. with stirring to obtain a mixture containing an asymmetric complex. To this mixture was added 5 g of 2- (2,5-dimethylphenoxymethyl) benzaldehyde, 0.21 g of trimethinoresilolinole cyanide and 15 mL of dichloromethane. The resulting mixture was stirred at an internal temperature of 0 ° C. for 1 hour, and then 0.84 g of hydrogen cyanide was added dropwise over 3 hours. The resulting mixture was stirred at 0 ° C for 3 hours to obtain a reaction mixture containing o- (2,5-dimethylphenoxymethyl) mandelonitrile. 3 wt with reaction mixture. After mixing with 5 g of / ₀ hydrochloric acid and allowing to stand, the organic layer was separated. The obtained organic layer was 3 wt. /. The organic layer was washed with 10 g of hydrochloric acid and then with 10 g of water to obtain 42.1 g of an organic layer containing optically active o- (2,5-dimethylphenoxymethyl) mandelonitrile.

Optically active o- (2,5-dimethylphenoxymethyl) Mandelonitrile content: 17.5% by weight

Optically active o- (2,5-dimethylphenoxymethyl) mandelonitrile yield: 90.1%

Optically active o- (2,5-dimethylphenoxymethyl) Mandeonitrile optical isomer excess ratio: 88% ee (R form) Example 9 To a 5 OmL three-necked flask, 96 mg of aluminum chloride, 0.32 g of 2,6-bis (4-1 (S) -monoloxazol-2-yl) pyridine, and 3 mL of dichloromethane were added. While stirring the obtained mixture, the internal temperature was adjusted to 0 ° C. to obtain a mixture containing an asymmetric complex. To the resulting mixture, 3 g of m-phenoxybenzaldehyde, 0.14 g of cyantrimethylsilyl and 1 OmL of dichloromethane were added. The resulting mixture was stirred at an internal temperature of 0 ° C. for 1 hour, and 0.57 g of hydrogen cyanide was added dropwise over 3 hours. After completion of the dropwise addition, the obtained mixture was further stirred at an internal temperature of 0 ° C. for 3 hours to obtain a reaction mixture containing m-phenoxymandelonitrile. The reaction mixture was mixed with 5 g of 3% by weight hydrochloric acid, allowed to stand, and then the organic layer was separated. The obtained organic layer was 3 wt. This was washed with 10 g of hydrochloric acid / ₀ and then with 10 g of water to obtain 22.5 g of an organic layer containing m-phenoxymandelonitrile.

Content of optically active m-phenoxymandelonitrile: 16.6% by weight

Yield of optically active m-phenoxymandelonitrile: 89.3%

Enantiomeric excess of optically active m-phenoxymandelonitrile: 65% e e (R form) Comparative Example 1 '

In Example 1, the reaction was carried out in the same manner as in Example 1 except that trimethylsilyl cyanide was not used. However, the reaction did not proceed and optically active o- (2,5-dimethylphenoxymethyl) mann Formation of delonitrile was not confirmed. Industrial applicability

According to the present invention, an optically active cyanohydrin compound can be obtained by using an asymmetric complex obtained from inexpensive aluminum halide, which is industrially advantageous.

Claims

The scope of the claims

Obtained by reacting an optically active pyridine compound represented by the formula (2) with an aluminum halide.

(Wherein Q ¹ and Q ² are independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkoxy group having 1 to 4 carbon atoms, the number of carbon atoms, An acyl group having 2 to 8 carbon atoms, an optionally substituted sulfonylsulfonyl group having 1 to 4 carbon atoms, an optionally substituted benzenesulfonyloxy group, a trialkyl having 1 to 10 carbon atoms A silyloxy group or an optionally substituted aryloxy group having 6 to 10 carbon atoms.)

Formula (3) characterized by reacting hydrogen cyanide with

(Wherein, Q 'and Q ² represents the same meaning as defined above, * represents that the carbon atom is an optically active center.)

A method for producing an optically active cyanohydrin compound represented by the formula:

2. The silyl compound is a trialkylsilyl cyanide compound. The manufacturing method as described.

3. The production method according to claim 1, wherein the silyl compound is trimethylsilyl cyanide.

4. The production method according to claim 1, wherein the aluminum halide is aluminum chloride.

5. One of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbon atoms. 1. The production method according to 1.

6. The production method according to claim 1, wherein one of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms.

7. Q ¹ is a hydrogen atom, Q ² is an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkoxy group having 1 to 4 carbon atoms, an acyl group having 2 to 8 carbon atoms An optionally substituted alkanesulfonyloxy group having 1 to 4 carbon atoms, an optionally substituted benzenesulfonyloxy group, a trialkylsilyloxy group having 1 to 10 carbon atoms, or a substituted group. The production method according to claim 1, which is an aryloxy group having 6 to 10 carbon atoms.

8. The Q ¹ is a hydrogen atom, and the Q ² is an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted aryl group having 6 to 10 carbon atoms. Manufacturing method.

9. The production method according to claim 1, wherein the amount of the asymmetric complex used is 0.0005 to 1 mol per 1 mol of the aldehyde compound represented by the formula (2) in terms of aluminum atom.

10. The production method according to claim 1, wherein the amount of the silyl compound used is 0.01 to 0.5 mol with respect to 1 mol of the aldehyde compound represented by the formula (2).

1 1. The production method according to claim 1, wherein the amount of hydrogen cyanide used is 1.1 to 3 mol per 1 mol of the aldehyde compound represented by the formula (2).